This invention relates to a process of mixing of crystalline cefuroxime axetil with amorphous cefuroxime axetil for the preparation of a bioavailable oral dosage form comprising of amorphous cefuroxime axetil containing from 7 to 25% crystalline cefuroxime axetil.
Cefuroxime axetil is a 1-acetoxyethyl ester of cefuroxime. It is a second generation cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram-negative microorganisms. This compound as well as many other esters of cefuroxime are disclosed and claimed in U.S. Pat. No. 4,267,320.
Crystalline cefuroxime axetil, however, does not exhibit adequate bioavailability upon oral administration. It is important that cephalosporin compounds for oral administration should be in a form which provides high bioavailability whereby absorption into the blood stream is maximized and the amount of antibiotic remaining in the gastrointestinal tract is minimized. Any antibiotic which is not absorbed will be therapeutically ineffective and by remaining in the gastrointestinal tract may cause side effects. An amorphous form of cefuroxime axetil which has high bioavailability has been described in U.S. Pat. No. 4,562,181. This form is essentially free from crystalline material. Related U.S. Pat. Nos. 4,820,833, 4,994,567, and 5,013,833 describe processes for the preparation of amorphous cefuroxime axetil.
U.S. Pat. No. 4,820,833 claims a process for preparing a highly pure, substantially amorphous form of cefuroxime axetil which comprises preparing a highly pure solution of cefuroxime axetil and spray drying it to recover highly pure substantially amorphous cefuroxime axetil.
U.S. Pat. No. 4,994,467 claims a process for the preparation of predominantly pure amorphous cefuroxime axetil which comprises recovering cefuroxime axetil from a solution thereof by roller drying.
U.S. Pat. No. 5,103,833 claims a process for the preparation of highly pure cefuroxime axetil in a predominantly amorphous form by solvent precipitation. The solvents claimed, however, require elevated temperatures for dissolving cefuroxime axetil.
Although solvent precipitation is a cheap and commercially viable method of preparing amorphous cefuroxime axetil, it suffers from the disadvantages of not yielding highly pure amorphous cefuroxime axetil, a form which is known to have high bioavailability. It is for this reason that the commercially available formulation of cefuroxime axetil, xe2x80x9cCeftin(trademark)xe2x80x9d, marketed by Glaxo is formulated from highly pure amorphous cefuroxime axetil produced by the spray drying method which is a very expensive process involving huge capital investments. Although highly pure amorphous cefuroxime axetil has been reported to have a higher bioavailability than crystalline cefuroxime axetil, it needs careful processing and cannot be processed by the commonly used wet granulation technique as the amorphous form gets converted to the crystalline form upon contact with water.
According to the present invention, we have studied the effect of different percentage of crystallinity in the amorphous cefuroxime axetil on the bioavailability of cefuroxime axetil formulations when compared with a formulation made up of highly pure amorphous cefuroxime axetil. Surprisingly, we found that tablets containing from 7 to 25% crystalline cefuroxime axetil together with amorphous cefuroxime axetil exhibited similar bioavailability profile as the tablets composed of pure amorphous cefuroxime axetil. This not only allows more flexibility in choosing the wet granulation technique for processing without fear of generating a small percentage of crystallinity in the tablet, it also allows the use of the cheaper and more commercially viable method of solvent precipitation of preparing predominantly amorphous cefuroxime axetil, which may contain up to 10% crystallinity as described in copending Indian application No. 2235/Del/98.
According to another aspect of the invention a sodium salt of citric acid, monosodium citrate, is added to the formulation containing cefuroxime axetil with different percentages of crystallinity. It is known in the art that when amorphous cefuroxime axetil comes in contact with water, it forms a gel which prolongs the disintegration and retards the dissolution in a tablet formulation. This property to form a gel is dependent upon the temperature, pH and ionic strength of the media. To get an optimum dissolution profile from the tablet, it is essential to reduce the ability of amorphous cefuroxime axetil to form a gel. We have observed that addition of a sodium salt of citric acid to the formulation containing amorphous cefuroxime axetil inhibits the tendency of amorphous cefuroxime axetil to form a gel. This may be due to the presence of citrate ions which prevents cefuroxime axetil molecules from bridging to form a gel, thereby helping in tablet dissolution.
These results are further illustrated by the examples described herein.